Gefitinib is an anilinoquinazoline which is useful in the treatment of a certain type of lung cancer (non-small cell lung cancer or NSCLC) that has not responded to chemotherapy. The chemical name for gefitinib is 4-(3′-chloro-4′-fluoroanilino)-7-methoxy-6-(3-morpholinopropoxy)quinazoline. Its structural formula is:

The earliest known synthesis of gefitinib was first disclosed in the patent application WO 96/33980. The synthetic method employed is depicted in the following reaction scheme 1.

The process involves selective demethylation of 6,7-dimethoxy quinazoline-4-one using methanesutfonic acid and L-methionine to get its 6-hydroxyl derivative, which is protected by acetylation. The acetoxy compound is chlorinated and condensed with chloro-fluoroaniline. Hydrolysis of the acetoxy compound followed by etherification with 3-morpholinopropyl chloride gives crude gefitinib which is purified by column chromatography. The process suffers from many disadvantages as it involves several protection and deprotection steps. The selective demethylation using methionine results in isomeric impurities and has to be purified or else the impurity carries over to subsequent steps in the preparation of gefitinib making it more difficult to isolate a pure product. The process also leads to formation of an N-alkylated impurity at the final stage which must be separated by column chromatography to obtain gefitinib.
Several other approaches are also described in the literature to make gefitinib.
WO 2004/024703 discloses a process for the preparation of gefitinib starting from 3-hydroxy-4-methoxy benzonitrile which involves condensation of 3-hydroxy-4-methoxy benzonitrile with morpholino propyl chloride, nitration, reduction with sodium dithionite to amino compound, hydrolysis of nitrile to amide, cyclisation in the presence of formamide to obtain quinazoline, chlorination with phosphorous oxychloride and finally condensation with chloro-fluoro aniline to obtain gefitinib. The process involves multiple steps and hence is time consuming.
WO 2005/023783 discloses a process for the manufacture of gefitinib starting from 2-amino-4-methoxy-5-(3-morpholinopropoxy)benzonitrile. The process involves a rearrangement reaction of 3-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)3,4-dihydroqunazoline-4-imine. The process is not feasible industrially, as the basic raw material is not readily available on a commercial scale and involves the use of excess 3-chloro-4-fluoroaniline which is expensive. A further draw back of the process is in the isomerization of the 4-imine compound which requires anhydrous conditions at high temperature for a longer duration of 96 hours. All the problems associated with this prior art process are overcome by the novel process of the present invention.
WO2005/070909 discloses a process for the preparation of gefitinib starting from isovanillin as depicted in scheme 2

The WO' 909 process has disadvantages as it forms cis-trans geometrical isomers of the oxime, which have different reactivities. Furthermore, the process uses a large excess of acetic anhydride to convert the oxime to the nitrile at higher temperature.
The patent applications 901/CHE/2006 and 903/CHE/2006 disclose another route for preparing gefitinib starting from isovanillin. The process involves formation of a formamido compound [N′-[2-cyano-4-{3-(4-morpholinyl)propoxy}phenyl]-N,N-dimethyl formamide], which is unstable and may result in undesired impurities in the final condensation with 3-chloro-4-fluoro aniline, thereby making the process less feasible on an industrial scale.
The processes disclosed in the prior art are cumbersome. Therefore, there exists a need for a more economical and efficient method of making gefitinib which is suitable for industrial scale-up.
The process of the present invention avoids use of reagents such as sodium dithionite, acetic anhydride and allows substantial reduction in the number of problems associated with these reagents.